Epoxyeicosatrienoic acids are involved in the C70fullerene derivative-induced control of allergic asthma

Background Fullerenes are molecules being investigated for a wide range of therapeutic applications. We have shown previously that certain fullerene derivatives (FDs) inhibit mast cell (MC) functionin vitro, and here we examine theirin vivotherapeutic effect on asthma, a disease in which MCs play a predominant role. Objective We sought to determine whether an efficient MC-stabilizing FD (C70-tetraglycolate ) can inhibit asthma pathogenesisin vivoand to examine itsin vivomechanism of action. Methods Asthma was induced in mice, and animals were treated intranasally with TGA either simultaneously with treatment or after induction of pathogenesis. The efficacy of TGA was determined through the measurement of airway inflammation, bronchoconstriction, serum IgE levels, and bronchoalveolar lavage fluid cytokine and eicosanoid levels. Results We found that TGA-treated mice have significantly reduced airway inflammation, eosinophilia, and bronchoconstriction. The TGA treatments are effective, even when given after disease is established. Moreover, we report a novel inhibitory mechanism because TGA stimulates the production of an anti-inflammatory P-450 eicosanoid metabolites (cis-epoxyeicosatrienoic acids ) in the lung. Inhibitors of these anti-inflammatory EETs reversed TGA inhibition. In human lung MCs incubated with TGA, there was a significant upregulation ofCYP1Bgene expression, and TGA also reduced IgE production from B cells. Lastly, MCs incubated with EET and challenged through FcεRI had a significant blunting of mediator release compared with nontreated cells. Conclusion The inhibitory capabilities of TGA reported here suggest that FDs might be used a platform for developing treatments for asthma.